PMID- 38029480
OWN - NLM
STAT- MEDLINE
DCOM- 20231218
LR  - 20240306
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 196
DP  - 2024 Jan
TI  - A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib 
      plus trametinib in patients with BRAF(V600) mutant advanced melanoma (INTERIM).
PG  - 113455
LID - S0959-8049(23)00758-X [pii]
LID - 10.1016/j.ejca.2023.113455 [doi]
AB  - BACKGROUND: BRAF+MEK inhibitors extend life expectancy of patients with 
      BRAF(V600) mutant advanced melanoma. Acquired resistance limits duration of 
      benefit, but preclinical and case studies suggest intermittent dosing could 
      overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent 
      dosing regimen. METHODS: Patients with BRAF(V600) mutant advanced melanoma due to 
      start dabrafenib+trametinib were randomised to receive either continuous (CONT), 
      or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A 
      composite primary endpoint included progression-free survival (PFS) and quality 
      of life (QoL). Secondary endpoints included response rate (ORR), overall survival 
      (OS) and adverse events (AEs). Mutant BRAF(V600E) ctDNA was measured by droplet 
      digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection 
      threshold. RESULTS: 79 patients (39 INT, 40 CONT) were recruited; median age 67 
      years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months 
      median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 
      10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached 
      (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients 
      experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs 
      (53 % vs 42 %). QoL favoured CONT. Detection of BRAF(V600E) ctDNA prior to 
      treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both 
      arms. A change to undetected during treatment did not significantly predict 
      better OS. CONCLUSION: INTERIM findings are consistent with other recent clinical 
      trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK 
      inhibitors.
CI  - Crown Copyright (c) 2023. Published by Elsevier Ltd. All rights reserved.
FAU - Dayimu, Alimu
AU  - Dayimu A
AD  - Clinical Trials Unit, Department of Oncology, University of Cambridge, Cambridge, 
      UK.
FAU - Gupta, Avinash
AU  - Gupta A
AD  - The Christie NHS Foundation Trust, Manchester, UK.
FAU - Matin, Rubeta N
AU  - Matin RN
AD  - Department of Dermatology, Churchill Hospital, Oxford University Hospitals NHS 
      Foundation Trust, Oxford, UK.
FAU - Nobes, Jenny
AU  - Nobes J
AD  - Department of Oncology, Norfolk and Norwich University Hospital NHS Foundation 
      Trust, Norfolk, UK.
FAU - Board, Ruth
AU  - Board R
AD  - Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Preston, UK.
FAU - Payne, Miranda
AU  - Payne M
AD  - Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation 
      Trust, Churchill Hospital, Oxford, UK.
FAU - Rao, Ankit
AU  - Rao A
AD  - Department of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, 
      UK.
FAU - Fusi, Alberto
AU  - Fusi A
AD  - Department of Medical Oncology, St George's University Hospitals NHS Foundation 
      Trust, London, UK.
FAU - Danson, Sarah
AU  - Danson S
AD  - Division of Clinical Medicine, The University of Sheffield, Sheffield, UK; 
      Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK.
FAU - Eccles, Bryony
AU  - Eccles B
AD  - Department of Medical Oncology, University Hospitals Dorset NHS Foundation Trust, 
      Poole, UK.
FAU - Carser, Judith
AU  - Carser J
AD  - Department of Oncology, Belfast Health and Social Care Trust, Belfast, UK.
FAU - Brown, Ciara O'Hanlon
AU  - Brown CO
AD  - St James's Hospital, Dublin, Ireland.
FAU - Steven, Neil
AU  - Steven N
AD  - Department of Oncology, University Hospitals Birmingham NHS Foundation Trust, 
      Birmingham, UK.
FAU - Bhattacharyya, Madhumita
AU  - Bhattacharyya M
AD  - Department of Oncology, Royal Berkshire NHS Foundation Trust, Reading, UK.
FAU - Brown, Ewan
AU  - Brown E
AD  - Western General Hospital, Lothian NHS Board, Edinburgh, UK.
FAU - Gonzalez, Michael
AU  - Gonzalez M
AD  - Department of Oncology, Imperial College Healthcare NHS Trust, London, UK.
FAU - Highley, Martin
AU  - Highley M
AD  - Oncology Centre, Derriford Hospital, University Hospitals Plymouth NHS Trust, 
      Plymouth, UK.
FAU - Pickering, Lisa
AU  - Pickering L
AD  - Skin and Renal Units, Royal Marsden NHS Foundation Trust, London, UK.
FAU - Kumar, Satish
AU  - Kumar S
AD  - Velindre Cancer Centre, Velindre University NHS Trust, Cardiff, UK.
FAU - Waterston, Ashita
AU  - Waterston A
AD  - Beatson West of Scotland Cancer Centre, Glasgow, UK.
FAU - Burghel, George
AU  - Burghel G
AD  - Manchester Centre for Genomic Medicine, Manchester University NHS Foundation 
      Trust, Manchester, UK.
FAU - Demain, Leigh
AU  - Demain L
AD  - Manchester Centre for Genomic Medicine, Manchester University NHS Foundation 
      Trust, Manchester, UK.
FAU - Baker, Eleanor
AU  - Baker E
AD  - Manchester Centre for Genomic Medicine, Manchester University NHS Foundation 
      Trust, Manchester, UK.
FAU - Wulff, Jerome
AU  - Wulff J
AD  - Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation 
      Trust, Cambridge, UK.
FAU - Qian, Wendi
AU  - Qian W
AD  - Clinical Trials Unit, Department of Oncology, University of Cambridge, Cambridge, 
      UK; Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation 
      Trust, Cambridge, UK.
FAU - Twelves, Sophie
AU  - Twelves S
AD  - Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation 
      Trust, Cambridge, UK.
FAU - Middleton, Mark
AU  - Middleton M
AD  - Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation 
      Trust, Churchill Hospital, Oxford, UK; Department of Oncology, University of 
      Oxford, Oxford, UK.
FAU - Corrie, Pippa
AU  - Corrie P
AD  - Oncology Department, Cambridge University Hospitals NHS Foundation Trust, 
      Cambridge, UK. Electronic address: philippa.corrie@nhs.net.
LA  - eng
GR  - 24579/CRUK_/Cancer Research UK/United Kingdom
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20231124
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - QGP4HA4G1B (dabrafenib)
RN  - 33E86K87QN (trametinib)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidinones)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 2.7.11.1 (BRAF protein, human)
SB  - IM
MH  - Humans
MH  - Aged
MH  - *Melanoma/drug therapy/genetics/pathology
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Quality of Life
MH  - Pyridones
MH  - Pyrimidinones
MH  - Mitogen-Activated Protein Kinase Kinases
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - Mutation
MH  - *Skin Neoplasms/drug therapy/genetics/pathology
OTO - NOTNLM
OT  - BRAF
OT  - Circulating tumour DNA
OT  - Continuous dosing
OT  - Dabrafenib
OT  - Intermittent dosing
OT  - Metastatic melanoma
OT  - Scheduling
OT  - Trametinib
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/30 00:42
MHDA- 2023/12/18 06:42
CRDT- 2023/11/29 18:01
PHST- 2023/09/05 00:00 [received]
PHST- 2023/11/07 00:00 [revised]
PHST- 2023/11/15 00:00 [accepted]
PHST- 2023/12/18 06:42 [medline]
PHST- 2023/11/30 00:42 [pubmed]
PHST- 2023/11/29 18:01 [entrez]
AID - S0959-8049(23)00758-X [pii]
AID - 10.1016/j.ejca.2023.113455 [doi]
PST - ppublish
SO  - Eur J Cancer. 2024 Jan;196:113455. doi: 10.1016/j.ejca.2023.113455. Epub 2023 Nov 
      24.